Dataset Information

Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing.

ABSTRACT:

Background

There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established.

Methods

In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n = 22-24 per group/region).

Findings

We found over 3000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in astrocytes, Drd3+MSNs and oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS).

Interpretation

Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross-disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS.

Funding

This work was supported by funding from the Hope for Depression Research Foundation (MJM).

SUBMITTER: Fitzgerald E

PROVIDER: S-EPMC10432187 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing.

Fitzgerald Eamon E Arcego Danusa Mar DM Shen Mo Jun MJ O'Toole Nicholas N Wen Xianglan X Nagy Corina C Mostafavi Sara S Craig Kelly K Silveira Patricia Pelufo PP Rayan Nirmala Arul NA Diorio Josie J Meaney Michael J MJ Zhang Tie-Yuan TY

EBioMedicine 20230805

<h4>Background</h4>There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established.<h4>Methods</h4>In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial ...[more]

PMID: 37549631

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Project description:BackgroundThere is an ongoing debate on whether sex affects immune-suppressive tumor microenvironment and immunotherapy. Here, we explored the underlying molecular bases for sex dimorphisms and their impact on the efficacy of immunotherapy in esophageal cancer (EC).Methods2360 EC patients from phase 3 trials were pooled to compare overall survivals by calculating hazard ratios (HRs) and their 95% confidence intervals (CIs). Genomic data of 1425 samples were integrated to depict the genomic landscapes and antigenic features. We also examined the sex disparities based on single-cell RNA sequencing and T cell receptor-sequencing data from 105,145 immune cells in 60 patients.ResultsImmunotherapy was associated with favorable outcomes in men (HR, 0.71; 95% CI, 0.65-0.79; P < 0.001), but not in women (HR, 0.98; 95% CI, 0.78-1.23; P = 0.84) (Pinteraction =0.02). The frequencies of 8 gene mutations, 12 single base substitutions signatures, and 131 reactome pathways were significantly different between male and female. Additionally, six subtypes of HLA-II antigens were enriched in women. Hence, we constructed and then validated a sex-related signature to better predict the outcomes of immunotherapy. Exhausted CD8+ T cells were highly infiltrated in men, while naïve CD8+ T cells were more common in women. Further examinations on multiple malignancies suggested exhausted CD8+ T cells were enriched in patients who responded to immunotherapy.ConclusionsOur study delineated the robust genomic and cellular sex disparities in EC. Furthermore, male, rather than female, derived significantly benefits from immunotherapy. These results have implications for treatment decision-making and developing immunotherapy for personalized care. In the past several years, immunotherapy has gradually replaced the traditional chemotherapy as the standard treatment in esophageal cancer. It is well-established that immunological responses in male and female differ significantly. However, there is an ongoing debate on whether sex can impact the treatment outcomes in immunotherapy. In the present study, we systematically characterized the genomic and cellular landscapes of esophageal cancer, and revealed the significant differences between male and female patients. Furthermore, with over 2000 patients with esophageal cancer, we showed that only men can benefit from immunotherapy. In women, immunotherapy failed to show superior over chemotherapy. These results have implications for treatment decision-making and developing next-generation immunotherapy for personalized care.

Dataset Information

Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing.

Background

Methods

Findings

Interpretation

Funding

Publications

Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing.

Similar Datasets

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